Cell differentiation inducing amide derivatives, their production and use

Abstract

The present invention provides a compound represented by the formula: wherein R 1 is an amino group which may be substituted; R 2 is a hydrogen atom or a lower alkyl group which may be substituted; X is a methyne group which may be substituted or N(O)m (m is 0 or 1); a ring A is a homo- or hetero-cycle which is substituted by a halogen atom, lower alkyl, lower alkoxy or lower alkylenedioxy; and a ring B is a homo- or hetero-cycle which may be substituted; or a salt thereof, which exhibits excellent cell differentiation-inducing action and cell differentiation-inducing factor action-enhancing action, and is useful in the treatment and prevention of various nerve diseases or bone/joint diseases.

What is claimed is:  
     
       1. A compound represented by the formula:                    
       wherein R 1  is an amino group which may be substituted by  
       (a) a C 1-6  alkyl group, C 2-6  alkenyl group, C 2-6  alkynyl group, C 3-6  cycloalkyl group, C 6-14  aryl group or C 7-16  aralkyl group, which may be substituted by a group selected from the group consisting of (i) a halogen atom, (ii) C 1-3  alkylenedioxy, (iii)nitro, (iv) cyano, (v) optionally halogenated C 1-6  alkyl, (vi) optionally halogenated C 2-6  alkenyl, (vii) optionally halogenated C 2-6  alkynyl, (viii) C 3-6  cycloalkyl, (ix) optionally halogenated C 1-6  alkoxy, (x) optionally halogenated C 1-6  alkylthio, (xi) hydroxy, (xii) amino, (xiii) mono-C 1-6  alkyl amino, (xiv) di-C 1-6  alkyl amino, (xv) 5 or 6 membered cyclic amino, (xvi) acyl amino selected from C 1-6  alkoxy-carbonyl amino, mono-C 1-6  alkylaminocarbonyl amino, C 1-6  alkylcarbonyl amino and C 1-6  alkylsulfonyl amino, (xvii) C 1-6  alkylcarbonyl, (xviii) carboxyl, (xix) C 1-6  alkoxy-carbonyl, (xx) carbamoyl, (xxi) mono-C 1-6  alkyl-carbamoyl, (xxii) di-C 1-6  alkyl-carbamoyl, (xxiii) C 6-10  aryl-carbamoyl, (xxiv) sulfo, (xxv) C 1-6  alkyl sulfonyl, (xxvi) C 6-10  aryl and (xvii) C 6-10  aryloxy,  
       (b) a hydroxy group which may be substituted by a C 1-6  alkyl group, C 2-6  alkenyl group, C 2-6  alkynyl group, C 3-6  cycloalkyl group, C 6-14  aryl group or C 7-16  aralkyl group, which may be substituted by a group selected from the group consisting of (i) a halogen atom, (ii) C 1-3  alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C 1-6  alkyl, (vi) optionally halogenated C 2-6  alkenyl, (vii) optionally halogenated C 2-6  alkynyl, (viii) C 3-6  cycloalkyl, (ix) optionally halogenated C 1-6  alkoxy, (x) optionally halogenated C 1-6  alkylthio, (xi) hydroxy, (xii) amino, (xiii) mono-C 1-6  alkyl amino, (xiv) di-C 1-6  alkyl amino, (xv) 5 or 6 membered cyclic amino, (xvi) acyl amino selected from C 1-6  alkoxy-carbonyl amino, mono-C 1-6  alkylaminocarbonyl amino, C 1-6  alkylcarbonyl amino and C 1-6  alkylsulfonyl amino, (xvii) C 1-6  alkylcarbonyl, (xviii) carboxyl, (xix) C 1-6  alkoxy-carbonyl, (xx) carbamoyl, (xxi) mono-C 1-6  alkyl-carbamoyl, (xxii) di-C 1-6  alkyl-carbamoyl, (xxiii) C 6-10  aryl-carbamoyl, (xxiv) sulfo, (xxv) C 1-6  alkyl sulfonyl, (xxvi) C 6-10  aryl and (xxvii) C 6-10  aryloxy, or  
       (c) an amino group which may be substituted by an acyl group represented by any one of the formula: —(C═O)—R 7 , —SO 2 —R 7 , —(C═O)NR 8 R 7 , —(C═O)O—R 7 , —(C═S)O—R 7  or —(C═S)NR 8 R 7  wherein R 7  is (a) hydrogen atom or (b) a C 1-6  alkyl group, C 2-6  alkenyl group, C 2-6  alkynyl group, C 3-6  cycloalkyl group, C 6-14  aryl group or C 7-16  aralkyl group, which may be substituted by a group selected from the group consisting of (i) a halogen atom, (ii) C 1-3  alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C 1-6  alkyl, (vi) optionally halogenated C 2-6  alkenyl, (vii) optionally halogenated C 2-6  alkynyl, (viii) C 3-6  cycloalkyl, (ix) optionally halogenated C 1-6  alkoxy, (x) optionally halogenated C 1-6  alkylthio, (xi) hydroxy, (xii) amino, (xiii) mono-C 1-6  alkyl amino, (xiv) di-C 1-6  alkyl amino, (xv) 5 or 6 membered cyclic amino, (xvi) acyl amino selected from C 1-6  alkoxy-carbonyl amino, mono-C 1-6  alkylaminocarbonyl amino, C 1-6  alkylcarbonyl amino and C 1-6  alkylsulfonyl amino, (xvii) C 1-6  alkylcarbonyl, (xviii) carboxyl, (xix) C 1-6  alkoxy-carbonyl, (xx) carbamoyl, (xxi) mono-C 1-6  alkyl-carbamoyl, (xxii) di-C 1-6  alkyl-carbamoyl, (xxiii) C 6-10  aryl-carbamoyl, (xxiv) sulfo, (xxv) C 1-6  alkyl sulfonyl, (xxvi) C 6-10  aryl and (xxvii) C 6-10  aryloxy, and R 8  is hydrogen atom or a C 1-6  alkyl group, or  
       (d) R 1  is a group formed by removing a hydrogen atom from a nitrogen atom of a 5 to 9 membered nitrogen-containing heterocycle which may have 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, other than carbon atoms and one nitrogen atom, and the nitrogen-containing heterocycle may be substituted by a group selected from the group consisting of (i) a halogen atom, (ii) C 1-3  alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C 1-6  alkyl, (vi) optionally halogenated C 2-6  alkenyl, (vii) optionally halogenated C 2-6  alkynyl, (viii) C 3-6  cycloalkyl, (ix) optionally halogenated C 1-6  alkoxy, (x) optionally halogenated C 1-6  alkylthio, (xi) hydroxy, (xii) amino, (xiii) mono-C 1-6  alkyl amino, (xiv) di-C 1-6  alkyl amino, (xv) 5 or 6 membered cyclic amino, (xvi) acyl amino selected from C 1-6  alkoxy-carbonyl amino, mono-C 1-6  alkylaminocarbonyl amino, C 1-6  alkylcarbonyl amino and C 1-6  alkylsulfonyl amino, (xvii) C 1-6  alkylcarbonyl, (xviii) carboxyl, (xix) C 1-6  alkoxy-carbonyl, (xx) carbamoyl, (xxi) mono-C 1-6  alkyl-carbamoyl, (xxii) di-C 1-6  alkyl-carbamoyl, (xxiii) C 6-10  aryl-carbamoyl, (xxiv) sulfo, (xxv) C 1-6  alkyl sulfonyl, (xxvi) C 6-10  aryl and (xxvii) C 6-10  aryloxy;  
       R 2  is a hydrogen atom;  
       X is a methyne group which may be substituted;  
       a ring A is a 4-10 membered homo-cycle which is substituted by a lower alkylenedioxy;  
       and a ring B is a homo- or hetero-cycle which may be substituted; or a pharmaceutically acceptable salt thereof.  
     
     
       2. The compound as claimed in  claim 1  wherein 
       X is CR 6  wherein R 6  is  
       (a) a hydrogen atom,  
       (b) a halogen atom,  
       (c) a C 1-6  alkyl group, C 2-6  alkenyl group, C 2-6  alkynyl group, C 3-6  cycloalkyl group, C 6-14  aryl group or C 7-16  aralkyl group which may be substituted by a group selected from the group consisting of (i) a halogen atom, (ii) C 1-3  alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C 1-6  alkyl, (vi) optionally halogenated C 2-6  alkenyl, (vii) optionally halogenated C 2-6  alkynyl, (viii) C 3-6  cycloalkyl, (ix) optionally halogenated C 1-6  alkoxy, (x) optionally halogenated C 1-6  alkylthio, (xi) hydroxy, (xii) amino, (xiii) mono-C 1-6  alkyl amino, (xiv) di-C 1-6  alkyl amino, (xv) 5 or 6 membered cyclic amino, (xvi) acyl amino selected from C 1-6  alkoxy-carbonyl amino, mono-C 1-6  alkylaminocarbonyl amino, C 1-6  alkylcarbonyl amino and C 1-6  alkylsulfonyl amino, (xvii) C 1-6  alkylcarbonyl, (xviii) carboxyl, (xix) C 1-6  alkoxy-carbonyl, (xx) carbamoyl, (xxi) mono-C 1-6  alkyl-carbamoyl, (xxii) di-C 1-6  alkyl-carbamoyl, (xxiii) C 6-10  aryl-carbamoyl, (xxiv) sulfo, (xxv) C 1-6  alkyl sulfonyl, (xxvi) C 6-10  aryl and (xxvii) C 6-10  aryloxy or  
       (d) —OR 6″  is (a′) a hydrogen atom or (b′) a C 1-6  alkyl group, C 2-6  alkenyl group, C 2-6  alkynyl group, C 3-6  cycloalkyl group, C 6-14  aryl group or C 7-16  aralkyl group which may be substituted by a group selected from the group consisting of (i) a halogen atom, (ii) C 1-3  alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C 1-6  alkyl, (vi) optionally halogenated C 2-6  alkenyl, (vii) optionally halogenated C 2-6  alkynyl, (viii) C 3-6  cycloalkyl, (ix) optionally halogenated C 1-6  alkoxy, (x) optionally halogenated C 1-6  alkylthio, (xi) hydroxy, (xii) amino, (xiii) mono-C 1-6  alkyl amino, (xiv) di-C 1-6  alkyl amino, (xv) 5 or 6 membered cyclic amino, (xvi) acyl amino selected from C 1-6  alkoxy-carbonyl amino, mono-C 1-6  alkylaminocarbonyl amino, C 1-6  alkylcarbonyl amino and C 1-6  alkylsulfonyl amino, (xvii) C 1-6  alkylcarbonyl, (xviii) carboxyl, (xix) C 1-6  alkoxy-carbonyl, (xx) carbamoyl, (xxi) mono-C 1-6  alkyl-carbamoyl, (xxii) di-C 1-6  alkyl-carbamoyl, (xxiii) C 6-10  aryl-carbamoyl, (xxiv) sulfo, (xxv) C 1-6  alkyl sulfonyl, (xxvi) C 6-10  aryl and (xxvii) C 6-10  aryloxy;  
       the ring A is a 4 to 10 membered cyclic hydrocarbon which is substituted by C 1-3  alkylenedioxy; and  
       the ring B is a 3 to 10 membered cyclic hydrocarbon or 5 to 9 membered heterocycle containing 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom other than carbon atoms, and the 3 to 10 membered cyclic hydrocarbon or 5 to 9 membered heterocycle may be substituted by a group selected from the group consisting of (i) a halogen atom, (ii) C 1-3  alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C 1-6  alkyl, (vi) optionally halogenated C 2-6  alkenyl, (vii) optionally halogenated C 2-6  alkynyl, (viii) C 3-6  cycloalkyl, (ix) optionally halogenated C 1-6  alkoxy, (x) optionally halogenated C 1-6  alkylthio, (xi) hydroxy, (xii) amino, (xiii) mono-C 1-6  alkyl amino, (xiv) di-C 1-6  alkyl amino, (xv) 5 or 6 membered cyclic amino, (xvi) acyl amino selected from C 1-6  alkoxy-carbonyl amino, mono-C 1-6  alkylaminocarbonyl amino, C 1-6  alkylcarbonyl amino and C 1-6  alkylsulfonyl amino, (xvii) C 1-6  alkylcarbonyl, (xviii) carboxyl, (xix) C 1-6  alkoxy-carbonyl, (xx) carbamoyl, (xxi) mono-C 1-6  alkyl-carbamoyl, (xxii) di-C 1-6  alkyl-carbamoyl, (xxiii) C 6-10  aryl-carbamoyl, (xxiv) sulfo, (xxv) C 1-6  alkyl sulfonyl, (xxvi) C 6-10  aryl and (xxvii) C 6-10  aryloxy.  
     
     
       3. The compound as claimed in  claim 1  wherein R 1  is a group represented by the formula:                    
       wherein R 3  and R 4  is the same or different and are independently a hydrogen atom, a hydroxy group which may be substituted, a lower alkyl group which may be substituted, an acyl group, an aryl group which may be substituted or an aralkyl group which may be substituted, or R 3  and R 4  may combine with an adjacent nitrogen atom and form a nitrogen-containing heterocyclic group which may be substituted.  
     
     
       4. The compound as claimed in  claim 3  wherein R 3  and R 4  are the same or different and are independently a hydrogen atom, a hydroxy group which may be substituted, a lower alkyl group which may be substituted or an acyl group, or R 3  and R 4  may combine with an adjacent nitrogen atom and form a nitrogen-containing heterocyclic group which may be substituted. 
     
     
       5. The compound as claimed in  claim 3  wherein R 3  and R 4  are the same or different and are independently a hydrogen atom or a lower alkyl group which may be substituted. 
     
     
       6. The compound as claimed in  claim 3  wherein R 3  is a hydrogen atom or a C 1-6  alkyl group, and R 4  is (i) a hydrogen atom or (ii) a C 1-6  alkyl group which may be substituted by a group selected from the group consisting of hydroxy, carboxyl, C 1-6  alkoxy-carbonyl, amino and mono- or d-C 1-6  alkyl amino, (iii) a C 6-14  aryl group which may be substituted by C 1-6  alkoxy or (iv) a C 7-16  aralkyl group which may be substituted by C 1-6  alkoxy or C 1-6  acylamino, or R 3  and R 4  combine with an adjacent nitrogen atom and form a 5 to 8 membered nitrogen-containing heterocyclic group which may be substituted by C 7-16  aralkyl. 
     
     
       7. The compound as claimed in  claim 1  wherein the ring A is a benzene ring which is substituted by a lower alkylenedioxy. 
     
     
       8. The compound as claimed in  claim 1  wherein the ring A is a C 6-10  aromatic hydrocarbon ring which is substituted by a C 1-3  alkylenedioxy. 
     
     
       9. The compound as claimed in  claim 1  wherein the ring B is a benzene ring which may be substituted. 
     
     
       10. The compound as claimed in  claim 1  wherein the ring B is (i) a C 6-12  aromatic hydrocarbon ring which may be substituted by a group selected from the group consisting of a halogen atom, optionally halogenated C 1-6  alkyl, optionally halogenated C 1-6  alkoxy and C 1-3  alkylenedioxy or (ii) a 5 to 8 membered heterocycle containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than carbon atoms, and the 5 to 8 membered heterocycle may be substituted by C 1-6  alkyl. 
     
     
       11. The compound as claimed in  claim 1  wherein R 1  is a group represented by the formula:                    
       wherein R 3′  is a hydrogen atom or a C 1-6  alkyl group, and R 4′  is (i) a hydrogen atom, (ii) a C 1-6  alkyl group which may be substituted by a group selected from the group consisting of hydroxy, carboxyl, C 1-6  alkoxy-carbonyl, amino and mono- or di-C 1-6  alkylamino, (iii) a C 6-14  aryl group which may be substituted by C 1-6  alkoxy or (iv) a C 7-16  aralkyl group which may be substituted by C 1-6  alkoxy or C 1-6  acylamino, or R 3′  and R 4′  may combine with an adjacent nitrogen atom and form a 5 to 8 membered nitrogen-containing heterocyclic group which may be substituted by C 7-16  aralkyl;  
       R 2  is a hydrogen atom;  
       X is a methyne group which may be substituted by C 1-6  alkyl;  
       the ring A is a C 6-10  aromatic hydrocarbon ring which is substituted by a C 1-3  alkylenedioxy; and  
       the ring B is (i) a C 6-10  aromatic hydrocarbon ring which may be substituted by a group selected from the group consisting of a halogen atom, optionally halogenated C 1-6  alkyl, optionally halogenated C 1-6  alkoxy and C 1-3  alkylenedioxy or (ii) a 5 to 8 membered heterocycle containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than carbon atoms, and the 5 to 8 membered heterocycle may be substituted by C 1-6  alkyl.  
     
     
       12. The compound as claimed in  claim 1  wherein R 1  is a group represented by the formula:                    
       wherein R 3″  is a hydrogen atom and R 4″  is a hydrogen atom or a C 7-16  aralkyl group which may be substituted by C 1-6  alkoxy;  
       R 2  is a hydrogen atom;  
       X is a methyne group;  
       the ring A is a C 6-10  aromatic hydrocarbon ring which is substituted by C 1-3  alkylenedioxy; and  
       the ring B is a C 6-10  aromatic hydrocarbon ring which may be substituted by a group selected from the group consisting of a halogen atom, C 1-6  alkoxy and C 1-3  alkylenedioxy.  
     
     
       13. A method for producing the compound as claimed in  claim 1  or a ester thereof, or a pharmaceutically acceptable salt thereof which comprises subjecting a compound represented by the formula:                    
       wherein each symbol is same as defined in  claim 1 , or a pharmaceutically acceptable salt thereof to an amidating reaction, and optionally followed by an acylating reaction.  
     
     
       14. A pharmaceutical composition which comprises the compound as claimed in  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. 
     
     
       15. A method for inducing cell differentiation or enhancing induction of cell differentiation of a mammalian cell which comprises administering to said mammalian cell an effective amount of a compound represented by the formula:                    
       wherein a ring A′ is a 4-10 membered homo-cycle which is substituted by a lower alkylenedioxy;  
       R 1  is an amino group which may be substituted by  
       (a) a C 1-6  alkyl group, C 2-6  alkenyl group, C 2-6  alkynyl group, C 3-6  cycloalkyl group, C 6-14  aryl group or C 7-16  aralkyl group, which may be substituted by a group selected from the group consisting of (i) a halogen atom, (ii) C 1-3  alkylenedioxy, (iii)nitro, (iv) cyano, (v) optionally halogenated C 1-6  alkyl, (vi) optionally halogenated C 2-6  alkenyl, (vii) optionally halogenated C 2-6  alkynyl, (viii) C 3-6  cycloalkyl, (ix) optionally halogenated C 1-6  alkoxy, (x) optionally halogenated C 1-6  alkylthio, (xi) hydroxy, (xii) amino, (xiii) mono-C 1-6  alkyl amino, (xiv) di-C 1-6  alkyl amino, (xv) 5 or 6 membered cyclic amino, (xvi) acyl amino selected from C 1-6  alkoxy-carbonyl amino, mono-C 1-6  alkylaminocarbonyl amino, C 1-6  alkylcarbonyl amino and C 1-6  alkylsulfonyl amino, (xvii) C 1-6  alkylcarbonyl, (xviii) carboxyl, (xix) C 1-6  alkoxy-carbonyl, (xx) carbamoyl, (xxi) mono-C 1-6  alkyl-carbamoyl, (xxii) di-C 1-6  alkyl-carbamoyl, (xxiii) C 6-10  aryl-carbamoyl, (xxiv) sulfo, (xxv) C 1-6  alkyl sulfonyl, (xxvi) C 6-10  aryl and (xvii) C 6-10  aryloxy,  
       (b) a hydroxy group which may be substituted by a C 1-6  alkyl group, C 2-6  alkenyl group, C 2-6  alkynyl group, C 3-6  cycloalkyl group, C 6-14  aryl group or C 7-16  aralkyl group, which may be substituted by a group selected from the group consisting of (i) a halogen atom, (ii) C 1-3  alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C 1-6  alkyl, (vi) optionally halogenated C 2-6  alkenyl, (vii) optionally halogenated C 2-6  alkynyl, (viii) C 3-6  cycloalkyl, (ix) optionally halogenated C 1-6  alkoxy, (x) optionally halogenated C 1-6  alkylthio, (xi) hydroxy, (xii) amino, (xiii) mono-C 1-6  alkyl amino, (xiv) di-C 1-6  alkyl amino, (xv) 5 or 6 membered cyclic amino, (xvi) acyl amino selected from C 1-6  alkoxy-carbonyl amino, mono-C 1-6  alkylaminocarbonyl amino, C 1-6  alkylcarbonyl amino and C 1-6  alkylsulfonyl amino, (xvii) C 1-6  alkylcarbonyl, (xviii) carboxyl, (xix) C 1-6  alkoxy-carbonyl, (xx) carbamoyl, (xxi) mono-C 1-6  alkyl-carbamoyl, (xxii) di-C 1-6  alkyl-carbamoyl, (xxiii) C 6-10  aryl-carbamoyl, (xxiv) sulfo, (xxv) C 1-6  alkyl sulfonyl, (xxvi) C 6-10  aryl and (xxvii) C 6-10  aryloxy, or  
       (c) an amino group which may be substituted by an acyl group represented by any one of the formula: —(C═O)—R 7 , —SO 2 —R 7 , —(C═O)NR 8 R 7 , —(C═O)O—R 7 , —(C═S)O—R 7  or —(C═S)NR 8 R 7  wherein R 7  is (a) hydrogen atom or (b) a C 1-6  alkyl group, C 2-6  alkenyl group, C 2-6  alkynyl group, C 3-6  cycloalkyl group, C 6-14  aryl group or C 7-16  aralkyl group, which may be substituted by a group selected from the group consisting of (i) a halogen atom, (ii) C 1-3  alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C 1-6  alkyl, (vi) optionally halogenated C 2-6  alkenyl, (vii) optionally halogenated C 2-6  alkynyl, (viii) C 3-6  cycloalkyl, (ix) optionally halogenated C 1-6  alkoxy, (x) optionally halogenated C 1-6  alkylthio, (xi) hydroxy, (xii) amino, (xiii) mono-C 1-6  alkyl amino, (xiv) di-C 1-6  alkyl amino, (xv) 5 or 6 membered cyclic amino, (xvi) acyl amino selected from C 1-6  alkoxy-carbonyl amino, mono-C 1-6  alkylaminocarbonyl amino, C 1-6  alkylcarbonyl amino and C 1-6  alkylsulfonyl amino, (xvii) C 1-6  alkylcarbonyl, (xviii) carboxyl, (xix) C 1-6  alkoxy-carbonyl, (xx) carbamoyl, (xxi) mono-C 1-6  alkyl-carbamoyl, (xxii) di-C 1-6  alkyl-carbamoyl, (xxiii) C 6-10  aryl-carbamoyl, (xxiv) sulfo, (xxv) C 1-6  alkyl sulfonyl, (xxvi) C 6-10  aryl and (xxvii) C 6-10  aryloxy, and R 8  is hydrogen atom or a C 1-6  alkyl group, or  
       (d) R 1  is a group formed by removing a hydrogen atom from a nitrogen atom of a 5 to 9 membered nitrogen-containing heterocycle which may have 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, other than carbon atoms and one nitrogen atom, and the nitrogen-containing heterocycle may be substituted by a group selected from the group consisting of (i) a halogen atom, (ii) C 1-3  alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C 1-6  alkyl, (vi) optionally halogenated C 2-6  alkenyl, (vii) optionally halogenated C 2-6  alkynyl, (viii) C 3-6  cycloalkyl, (ix) optionally halogenated C 1-6  alkoxy, (x) optionally halogenated C 1-6  alkylthio, (xi) hydroxy, (xii) amino, (xiii) mono-C 1-6  alkyl amino, (xiv) di-C 1-6  alkyl amino, (xv) 5 or 6 membered cyclic amino, (xvi) acyl amino selected from C 1-6  alkoxy-carbonyl amino, mono-C 1-6  alkylaminocarbonyl amino, C 1-6  alkylcarbonyl amino and C 1-6  alkylsulfonyl amino, (xvii) C 1-6  alkylcarbonyl, (xviii) carboxyl, (xix) C 1-6  alkoxy-carbonyl, (xx) carbamoyl, (xxi) mono-C 1-6  alkyl-carbamoyl, (xxii) di-C 1-6  alkyl-carbamoyl, (xxiii) C 6-10  aryl-carbamoyl, (xxiv) sulfo, (xxv) C 1-6  alkyl sulfonyl, (xxvi) C 6-10  aryl and (xxvii) C 6-10  aryloxy;  
       R 2  is a hydrogen atom;  
       X is a methyne group which may be substituted;  
       and a ring B is a homo- or hetero-cycle which may be substituted, or a pharmaceutically acceptable salt thereof to a mammalian cell.  
     
     
       16. A method as claimed in  claim 15  wherein the ring A′ is a 3 to 10 membered cyclic hydrocarbon. 
     
     
       17. A method of  claim 15  wherein the mammalian cell is in a mammal suffering from a nerve disease or bone/joint disease. 
     
     
       18. A method as in  claim 17  wherein said mammal is suffering from a nerve disease selected from a group consisting of nerve degeneration as found in cerebrovascular dementia, senile dementia, or Alzheimer's disease; amyotrophic lateral aclerosis; diabetic peripheral neuropathy; and Parkinson's disease. 
     
     
       19. The compound as claimed in  claim 1 , wherein the ring A is a homo-cycle which is substituted by a C 1-6  alkylenedioxy group. 
     
     
       20. The compound as claimed in  claim 1 , wherein R 1  is (i) an amino group which may be substituted by (a) a hydrocarbon group which may be substituted, (b) a hydroxy group which may be substituted or (c) an acyl group or (ii) a nitrogen-containing heterocyclic group which has a binding site on a ring-component nitrogen atom, optionally having substituents.